The major goal of applying nanotechnology in the medical industry is to change the surface of nanoparticles by utilizing their special qualities to create targeted, regulated release, simple-to-detect drug transport carriers, and a novel way to treat local lesions [23]. Because of their versatility in targeting tissues, capacity to reach deep molecular targets, and potential for prolonged drug release, nanoparticles are receiving much interest from pharmaceutical professionals in drug delivery investigations. Chitosan is a bioadhesive that is water soluble and easily adheres to negatively charged surfaces such as mucosal membranes. Chitosan is a biodegradable material that significantly improves the transport of polar medicines through epithelial surfaces. Because of its characteristics, chitosan can be employed to transport drugs [24]. Therefore, hespertin nanoparticles (HSPCNPs) were produced in the current work using chitosan polymer. Hesperetin is often praised for its anti-inflammatory and antioxidant characteristics. Nonetheless, because it has restricted solubility and bioavailability, it became essential to encapsulate it within carrier molecules, such as chitosan polymers. To increase the bioavailability and therapeutic efficacies of chitosan, hesperetin was loaded into nanoparticles in this research [25]. The main goal of this study was to investigate whether the oral administration of HSPCNPs to diabetic rats could improve the biochemical alterations in glucose metabolism.
T2DM is thought to be well-represented in Wistar rats that have undergone HFD/STZ induction. In the current investigation, rats were fed a high-fat diet for 4 weeks, after which a small dosage of STZ (35 mg/kg b.w) was injected. We next assessed the antidiabetic efficacy of HSPCNPs in this paradigm [26]. The basic characteristics of T2DM are weight loss, polyphagia, polyuria, and polydipsia. Because of the increased protein catabolism that occurred to provide the amino acids needed for gluconeogenesis when insulin was insufficient, muscular mass was lost. According to the study's findings, in contrast to the control group, animals given an HFD had significantly lower body weight and much higher water and food consumption. The breakdown of proteins and lipids in the tissues brought on by a lack of insulin is assumed to be the reason for the body's decreased weight. Increased water consumption causes hyperglycemia, which causes an abnormal loss of glucose through excessive excretion [27, 28]. However, HSPCNPs dramatically decreased body weight, and the symptoms of polyuria, polyphagia, and polydipsia were found in diabetic Wistar rats. The doses of 20 and 40 mg/kg are fixed by oral administration of HSPCNPs. It could be the outcome of better glucose control management in diabetic Wistar rats [29]. Rats with diabetes that had been artificially created exhibited severe hyperglycemia consistent with a reduction in endogenous insulin production. HbA1c significantly increased while hemoglobin levels were further lowered. An essential indicator for tracking diabetes mellitus is the assessment of glycosylated haemoglobin. A rise in blood glucose levels and a reaction between dicarbonyl molecules and haemoglobin that produces glycosylated haemoglobin cause the onset of diabetes complications [30]. This condition encourages an increase in glycosylated haemoglobin and a decrease in total haemoglobin levels. The considerable reduction in blood glucose levels seen in HSPCNP-treated rats may be the result of enhanced insulin release from pancreatic beta cells. In addition, when HSPCNP was administered to diabetic rats, Hb levels dramatically increased and HbA1c levels decreased in comparison to the control group and the metformin-treated group. This results from the blood glucose level returning to normal and Hb becoming less glycosylated [31].
The liver is a crucial organ that is essential for glycolysis and gluconeogenesis. A partial or complete lack of insulin perturbs the metabolism of carbohydrates, which in turn reduces the activity of glucokinase, impairing peripheral glucose uptake and increasing hepatic glucose synthesis. Insulin controls the activity of multiple metabolic enzymes to modulate the absorption and utilization of glucose in target organs such as the liver, kidney, skeletal muscle, and adipose tissue [32, 33]. An isoenzyme called hexokinase catalyzes the conversion of glucose to glucose-6-phosphate, playing an essential role in tissue intermediate metabolism. Mammalian hexokinases are engaged in the oxidation of glucose in four different isoforms. Hepatic hexokinase has been shown to have a significant influence on the utilization of glucose and the creation of glycogen in isolated hepatocytes and animal models of diabetes. Insulin treatment quickly restores hepatocyte hexokinase activity. These results indicate the restoration of hepatic hexokinase activity as a viable therapeutic strategy for the treatment of diabetes. Since insulin insufficiency is a defining characteristic of diabetes, the significantly reduced amount of insulin in the STZ-induced diabetic rats eventually results in the impairment of hexokinase function. However, the slight increase in hexokinase activity seen in diabetic animals given HNPCNPs protects the hepatic and extrahepatic tissues against STZ-induced diabetes by stimulating insulin production from the remaining cells, as STZ specifically kills cells in the pancreas. This study also showed that a slight increase in the activity of the enzyme hexokinase in the liver and kidney improves glucose metabolism and supports overall glucose homeostasis [34, 35].
A crucial enzyme in the homeostatic control of blood glucose levels, glucose-6-phosphatase is mostly expressed in the liver and kidney and is essential for supplying glucose to other organs during diabetes, extended fasting, or famine. It catalyzes the last stage in gluconeogenesis and glycogenolysis, the dephosphorylation of glucose-6 phosphate to free glucose. Insulin inhibits glucose-6-phosphatase activity whereas cAMP stimulates it. Experimental diabetic rats have an insulin shortage, which enhances glucose-6-phosphatase activity. Glucose-6-phosphatase activity increases hepatic glucose synthesis while decreasing hepatic glucose utilization. The increased hepatic glucose production in STZ-induced diabetic rats likely results from the dysregulation of the kidney and liver glucose-6-phosphatases, as evidenced by the close to normal activity in the diabetic rats given HSPCNPs treatment [36]. PEPCK regulates blood glucose levels because an excessive rate of endogenous glucose production is the major contributor to hyperglycemia in diabetes. PEPCK increased considerably. The production of the enzyme is directly correlated with PEPCK activity, and a positive association between plasma glucose levels and PEPCK has been established, suggesting its connection to hyperglycemia. Similarly, diabetic rats had less glucose-6 phosphate activity [37].
The decreased glucose-6-phosphate dehydrogenase activity in diabetic rats' liver tissues points to a diminished involvement of the phosphogluconate oxidation pathway in glucose metabolism. According to reports, glucose 6-phosphate dehydrogenase activity is reportedly increased by insulin in a dose-dependent manner. In our investigation, injection of HSPCNPs dramatically boosted insulin secretion, which in turn increased the activity of glucose 6-phosphate dehydrogenase [38].
The major regulator of hepatic gluconeogenesis, fructose-1,6-bisphosphatase, has been identified as a target for effective and secure glycemic control in diabetes. In this study, we discovered that it greatly increased activity in the diabetic rat liver, probably as a result of insulin deprivation. In diabetic rats, increased fructose-1,6-bisphosphatase activity was more effectively reversed after administration of HSPCNPs [39].
The main intracellular form of glucose that may be stored is called glycogen, and the amount of glycogen in different organs is a direct indicator of the degree of insulin activity since insulin encourages the deposition of intracellular glycogen by activating glycogen synthase and decreasing glycogen phosphorylase. The presence of glycogen, which is directly regulated by insulin, is a significant sign of the severity of diabetes. Glycogen synthase is stimulated and glycogen phosphorylase is inhibited by insulin, which results in the accumulation of glycogen in the liver and skeletal muscle. The glycogen content in the liver and skeletal muscles of diabetic rats was lowered due to decreased glycogen synthase activity, which occurs in the disease [40]. HSPCNP treatment boosted insulin production, increased glycogen synthase activity, and improved glycogen content in diabetic-treated rats, all of which helped reduce blood sugar levels.